Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cell Administration (REALIST-COVID) Phase 2 Randomised Controlled Trial

Abstract

RATIONALE Mesenchymal stromal cells (MSCs) have immunomodulatory and reparative effects which may be of benefit in acute respiratory distress syndrome (ARDS). The REALIST phase 1 study demonstrated safety of ORBCEL‐C MSCs in patients with ARDS.1 The REALIST COVID phase 2 study investigated the safety and efficacy of ORBCEL‐C MSCs in patients with ARDS due to COVID‐19. METHODS This was a multicentre, randomised, double‐blind, allocation concealed, placebo‐controlled trial in mechanically ventilated patients with moderate to severe ARDS, due to COVID‐19. Participants were randomised (1:1) to receive either ORBCEL‐C (CD362 enriched umbilical cord‐derived MSCs, 400x106 cells) or placebo (Plasma‐Lyte‐148). The primary safety outcome was the incidence of serious adverse events (SAEs). The primary efficacy outcome was oxygenation index (OI) at day 7. Secondary surrogate outcomes included OI at day 4 and day 7, respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score on days 4, 7, and 14. Clinical outcomes (including duration of ventilation and mortality) are reported. Patients were followed up at 1 year for mortality and significant medical events. Trial registration NCT03042143. RESULTS 60 participants were recruited from 2nd April until 4th December 2020 (the final analysis included n=30 in ORBCEL‐C and n=29 in placebo groups as n=1 in placebo group withdrew consent). Groups were balanced at baseline. There were 6 SAEs in the ORBCEL‐C and 3 in the placebo group, risk ratio (RR) 2.9(95% confidence interval (CI) 0.6‐13.2, p=0.25). There was no difference in OI at day 7 between the ORBCEL‐C (mean(SD) 98.3(57.2)) and placebo groups (mean(SD) 96.6(67.3): mean difference 1.8(95% CI 30.7‐34.4, p=0.91). There were no differences between groups in surrogate secondary outcomes (Figure 1). Clinical outcomes were underpowered, however there was no difference in mortality (28‐day mortality ORBCEL‐C 16.7% (n=5), placebo 20.7%(n=6); RR 0.8(95% CI 0.3‐2.4), p=0.69) and an increased duration of ventilation in the ORBCEL‐C group compared to placebo (ORBCEL‐C 19 days (IQR 13‐30), placebo 12 days (IQR 7‐20); hazard ratio 0.5(95% CI 0.3‐0.9), p=0.017). CONCLUSIONS This phase 2 trial supports the safety of ORBCEL‐C in patients with moderate to severe ARDS due to COVID‐ 19 but did not demonstrate efficacy, and does not support routine administration of ORBCEL‐C MSCs in this population. FUNDING Wellcome Trust Health Innovation Challenge Fund (reference 106939/Z/15/Z) and the Northern Ireland Health and Social Care Research and Development Fund. 1.Gorman E et al. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.